Non-thiol farnesyltransferase inhibitors: the concept of benzophenone-based bisubstrate analogue farnesyltransferase inhibitors

Replacement of the thiol in a benzophenone-based CAAX-peptidomimetic farnesyltransferase inhibitor by a carboxylic acid moiety resulted in a marked drop in inhibitory potency. Transformation of these carboxylic acid derivatives into bisubstrate analogues by addition of a lipophilic alkyl chain, which should be able to occupy considerable portions of the farnesyl binding region in the farnesyltransferase's active site, resulted in a regain of the inhibitory activity. These bisubstrate analogues represent new lead structures for non-thiol farnesyltransferase inhibitors. (C) 2000 Editions scientifiques et medicales Elsevier SAS.